Process for the preparation of 3-cyano-1-naphthoic acid and some analogues thereof

ABSTRACT

The present invention is related to a process for the preparation of 3-cyano-1-naphthoic acid and some analogues thereof of formula (1), the intermediate 1-halo-3-cyano naphthalene and some analogues thereof used in this process and a process for the preparation of said intermediate.

FIELD OF THE INVENTION

The present invention is related to a process for the preparation of3-cyano-1-naphthoic acid and some analogues thereof, the intermediate1-halo-3-cyano naphthalene and some analogues thereof used in thisprocess and a process for the preparation of said intermediate.

BACKGROUND OF THE INVENTION

The compound 3-cyano-1-naphthoic acid is previously described in JeffreyS. Albert et al; “Design, Synthesis, and SAR of Tachykinin AntagonistActivity”, J. Med. Chem, Vol. 45, no. 18, 2002, p. 3972-3983, p. 3973Scheme 2; p. 3980-3981, no 18-20, Richtzenhain Hermann et al:“Substitution reactions with metalloorganic compounds. IV. TheGrignardization of methoxyl-containing aromatic nitrites”; STNInternational, File CASREACT, Accession no. 44:10012, & Chem. Ber(1949), 82; 408-17, WO 01/77069, WO 00/59873, WO 00/20003, WO 00/20389,WO 02/12168, WO 01/77089 and WO 00/02859 and a process for thepreparation of the same is previously described in Jeffrey S. Albert etal; “Design, Synthesis, and SAR of Tachykinin Antagonist Activity”, J.Med. Chem, Vol. 45, no. 18, 2002, p. 3972-3983, p. 3973 Scheme 2; p.3980-3981, no 18-20, WO 01/77069, WO 00/59873, WO 00/20003, WO 00/20389,WO 02/12168 and WO 01/77089. This process is unattractive for commercialmanufacture on account of toxic process effluent arising from use ofmercury salt to achieve regioselective decarboxylation, low throughprocess yield and operationally unattractive bromination in concentratednitric acid.

BRIEF DESCRIPTION OF THE INVENTION

The present invention refers to a process for preparing the compound offormula (1)

wherein X and/or Y₁ and/or Y₂ are independently H, cyano, nitro,trifluoromethoxy, trifluoromethyl, alkoxy, or alkyl and R is H or alkyleither

-   a) in the case where R═H, by metallo-dehalogenation followed by    carboxylation of a compound of formula (12)    wherein X, Y₁ and Y₂ are as defined above, and Hal is Br, I or Cl or-   b) in the case where R═H or alkyl, by palladium mediated    carbonylation of a compound of formula (12)    with the proviso that the compound    1-iodo-3-cyano-2-methoxynaphthalene is excluded, followed by    solvolysis.

Furthermore the present invention refers to a compound of formula (12)

wherein X and/or Y₁ and/or Y₂ are independently H, cyano, nitro,trifluoromethoxy, trifluoromethyl, alkoxy, or alkyl and Hal is Br, I orCl, which is a compound not previously described and which is a keyintermediate in the preparation of the compound of formula (1,R═X═Y₁═Y₂═H) and moreover to a process for preparing a compound offormula (12, Y₁═Y₂═X═H).

Moreover the present invention refers to some other intermediates thatmay be used in the process for preparing the compound of formula (1,R═X═Y₁═Y₂═H), namely the compound of formula (20)

the compound of formula (18)

3-bromo-5-coumalonitrile (27)

and the compound of formula (63)

DETAILED DESCRIPTION OF THE INVENTION

The process for preparing the compound of formula (1)

wherein X and/or Y₁ and/or Y₂ are independently H, cyano, nitro,trifluoromethoxy, trifluoromethyl, alkoxy, or alkyl and R is H or alkylis carried out either

-   a) (in the case where R═H) by metallo-dehalogenation followed by    carboxylation of a compound of formula (12)    wherein X, Y₁ and Y₂ are as defined above, and Hal is Br, I or Cl or-   b) (in the case where R═H or alkyl) by palladium mediated    carbonylation of a compound of formula (12)    with the proviso that the compound    1-iodo-3-cyano-2-methoxynaphthalene is excluded, followed by    solvolysis.    Metallo-Dehalogenation and Carboxylation of Compound of Formula (12)

Metallo-dehalogenation and carboxylation may be carried out by treatmentof compound (12) with alkyl-lithium reagent, e.g. “BuLi, in THF alone orin admixture with solvents like hexane at a temperature below −10° C.,and preferably between −30° C. and −75° C., followed by reaction of thelithiated intermediate with CO₂ and subsequent acidification with e.g.HCl.Palladium Mediated Carbonylation

The halo-cyano-naphthalene (12) may be reacted with carbon monoxideunder elevated pressure, for example between 5 bar and 100 bar, in asolvent such as methanol with an organic base such as triethylaminecatalysed by palladium with or without additional phosphine ligand suchas triphenyl phosphine or bis-diphenylphosphino propane. The activepalladium catalyst can be generated in situ from palladium salts such aspalladium (II) chloride or palladiumbis(triphenylphosphine)palladium(In) chloride. The product (1) may beisolated by first of all removing solid residues by filtration and thenextracting into aqueous and back into organic with pH control, followedby crystallisation from toluene. The product (6) may be isolated byremoving solid residues by filtration followed by crystallisation fromsolvent.The Process for Preparing the Compound of Formula (12. Y₁═Y₂═X═H)

wherein Hal is Br, I or Clmay be carried out by any of the following routes:(i)by

-   (a) treating malic acid (7) with oleum or alternative strongly acid    dehydrating media to give coumalic acid (8);-   (b) esterifying coumalic acid (8) to give a pyrone ester (9);-   (c) brominating the pyrone ester (9) to give a 3-bromo coumalic    ester (10);-   (d) reacting the 3-bromo coumalic ester (10) with in situ generated    benzyne followed by decarboxylation to give a bromonaphthoate (11);    and-   (e) converting/transforming the bromonaphthoate (11) to    1-bromo-3-cyano naphthalene (12, Y₁═Y₂═X═H)    or (ii)    by-   (a) treating malic acid (7) with oleum or alternative strongly acid    dehydrating media to give coumalic acid (8);-   (b) converting coumalic acid (8) into coumalonitrile (25) and    subsequently brominating to give 3-bromo-5-coumalonitrile (27); and    then-   (c) converting 3-bromo-5-coumalonitrile (27) into 1-bromo-3-cyano    naphthalene (12, Y₁═Y₂═X═H)    by cycloaddition of in situ generated benzyne, followed by    subsequent decarboxylation    or (iii)    by-   1a) cyanation of 1,2,3,4-tetrahydronaphthalene followed by    bromination to give the compound of formula (63)-   1b) bromination of 1,2,3,4-tetrahydronaphthalene followed by    cyanodebromination, followed by bromination to give the compound of    formula (63); or-   1c) bromination of 1,2,3,4-tetrahydronaphthalene followed by    metallation and carboxylation followed by conversion to the    6-cyano-1,2,3,4-tetrahydronaphthalene followed by bromination to    give the compound of formula (63);    followed by-   2) oxidative aromatization of the compound of formula (63) into    1-bromo-3-cyano naphthalene (12, Y₁═Y₂═X═H);    which are illustrated in the reaction schemes below.

Stage (a)—Coumalic Acid

Oleum or alternative strongly acid dehydrating media is added to asuspension of malic acid in a strong acid e.g. H₂SO₄ at about 50° C. to90° C., preferably at 75° C. to 85° C. Then the mixture is cooled andthe product coumalic acid is filtered off.

Coumalic acid (8) is also commercially available.

Stage (b)—Pyrone Ester

Diisopropylethylamine or other non-nucleophilic base (e.g. DBU) is addedto a suspension of coumalic acid in NMP, dimethylsulphate (or else MeBror MeI) and a non-nucleophilic base, e.g. DBU or ^(i)Pr₂Net, are added,and the reaction stirred at between 20° C. and 30° C. The reaction massis diluted, e.g. with toluene, and drowned out into water followed bywashing of the organic phase with aqueous bicarbonate and finally water.The solvent is removed by evaporation in vacuo and the crude productpyrone ester is purified by filtration isolation from the residualmother liquors.

Stage (c)—3-Bromo Coumalic Acid

Pyrone ester is brominated, e.g. with pyridinium bromide perbromide(pyridinium tribromide) or Br₂ in glacial acetic acid to give 3-bromocoumalic acid.

Stage (d)—Bromonaphthoate

Isoamyl nitrite and a solution of anthranilic acid in e.g. ethyleneglycol dimethyl ether are is added to a refluxing solution of a 3-bromocoumalic ester in e.g. ethylene glycol dimethyl ether in the presence ofan acid, e.g. catalytic trichloroacetic acid. Benzene-2-diazoniumcarboxylate is formed by anthranilic acid diazotisation followed by insitu decomposition to give benzyne. The reactive benzyne undergoes [4+2]cycloaddition with the 3-bromo coumalic ester to give an intermediate(15), which then extrudes carbon dioxide to give the desiredbromonaphthoate. Heating under reflux is continued, the reaction mass isthen cooled to about 50° C., a solvent, e.g. toluene is added and themixture then cooled to ambient. The solution is washed with dilutesodium hydroxide solution, sodium bisulphite solution, water,hydrochloric acid and water again. The solution is then concentrated invacuo to give the crude bromonaphthoate product.

Stage (e)—1-Bromo-3-Cyano naphthalene

Three methods for this transformation are possible:

Method 1: Conversion to the Amide (18) Followed by Dehydration

Bromonaphthoate (11) is heated with ammonia in the presence of asolvent, e.g. toluene; and a catalyst, e.g. KI, at a high temperature togive bromoamide (18) This is followed by dehydration by heating thebromoamide in a large excess of a dehydrating agent, e.g. SOCl₂, to givethe compound of formula (12).

Method 2: Conversion to the Hydroxamic Acid (20)

Preparation of hydroxamic acid (20) is achieved by reaction of abromonaphthoate (11) with hydroxylamine, or a salt thereof, e.g.hydrochloride plus added base. Conversion of the hydroxamic acid (20) to1-bromo-3-cyano naphthalene (12) is effected by dehydration, e.g. bytreatment with PBr₃.

Method 3: Direct Conversion of Bromonaphthoate (11) to 1-bromo-3-cyanonaphthalene (12, X═Y₁═Y₂═H) with Me₂AlNH₂ (21)

The reagent for this transformation, dimethylaluminium amide, isprepared under strictly anhydrous conditions in an inert atmosphere bycondensing anhydrous NH₃ into a solution of AlMe₃ at low temperature.

A solution of Me₂AlNH₂ solution is added to a solution of abromonaphthoate in a high-boiling solvent, e.g. m-xylene, and themixture is heated to reflux. Rapid conversion to the 1-bromo-3-cyanonaphthalene (12) occurs and the product is isolated.

Route (ii)

Stage (a)—Coumalic Acid: See Route (i) Stage (a) Above Stage(b)—3-bromo-5-coumalonitrile

Coumalic acid (8) is converted to the corresponding nitrile (25) byconversion to the acid chloride (28) by reaction with a chlorinatingagent, e.g. thionyl chloride, followed by reaction with sulfamide(H₂NSO₂NH₂).

Coumalonitrile (25) is brominated using a brominating agent, e.g.pyridinium bromide perbromide (PBPB) in a high-boiling solvent to givebromocoumalonitrile (27). The product is isolated from unreactedstarting material by crystallisation.

Stage (c)—1-Bromo-3-Cyano naphthalene

Compound (27) is converted into compound (12) by cycloaddition of insitu generated benzyne, followed by subsequent decarboxylation e.g. byheating.

The presence of a cyano—rather than an ester group at the 5-position ofpyrone ring does not affect the progress of the cycloaddition.

Route (iii)

1,2,3,4-tetrahydronaphthalene (also known as Tetralin®) is cyanated togive cyanotetrahydronaphthalene (70), either directly by reaction withcyanogen bromide with aluminium chloride as catalyst in carbondisulphide, or via bromotetrahydronaphthalene (68), the resulting cyanotetrahydronaphthalene (70) is brominated to givebromocyanotetrahydronaphthalene (63) which is converted tobromocyanonaphthalene (12) by oxidative aromatisation.

Thus, tetrahydronaphthalene (59) is reacted with bromine, with addediodine as catalyst, the 6-bromo-1,2,3,4-tetrahydronaphthalene (plusregioisomers) is either a) cyanated by reaction with copper (I) cyanidein NMP at 130° C. for 48 h to give 6-cyano-1,2,3,4-tetrahydronaphthalene(70) or b) is lithiated by reaction with n-butyl lithium in THF at −78°C. followed by reaction with carbon dioxide and then dilute hydrochloricacid to furnish 5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (69)along with its regioisomer from which tetrahydronaphthalene acid (69) ispurified by repeated recrystallisation. This acid is converted tocyanonaphthalene (70) by conversion to acid chloride by reaction withthionyl chloride with a small amount of NMP as catalyst, followed byconversion to amide by reaction with ammonia, followed by amidedehydration, for example with PBr₃.5,6,7,8-Tetrahydronaphthalene-2-carbonitrile (70) is brominated byreaction with bromine with catalytic ferric bromide in carbontetrachloride to give bromonitrile (63).Aromatisation of Substituted Tetralins

The aromatisation of the compound of formula (63) into the compound offormula (12) is carried out by heating the compound of formula (63) at ahigh temperature in the presence of a metal catalyst, e.g. Pd/C.Alternatively, the aromatisation may be carried out for example bystirring with elemental sulphur in a solvent at ambient temperature.

PREPARATIONS Preparation 1

Conversion of malic acid to coumalic acid Oleum (287 g) is addeddropwise over 2 h to a suspension of malic acid (200 g) in concentratedH₂SO₄ (313 g) at 75° C. and the resulting solution stirred for a further4 h, maintaining temperature at 75° C. throughout. The mixture is cooledand then drowned out into ice-cold water over 1 h. After stirring for 15min and standing overnight, the mixture is cooled to below 10° C. andthe product is isolated by filtration to give coumalic acid (71 g, 95%purity, 65% yield) after washing and drying.

Preparation 2

Conversion of coumalic acid to coumalic acid, methyl esterDiisopropylethylamine is added to a suspension of coumalic acid (115.5g) in N-methylpyrrolidone (600 mL) at 25° C., dimethylsulphate (100.9 g)is added over 1 h and the reaction stirred at 25° C. for 2 h. Thereaction mass is diluted with toluene, and extracted with water thenbicarbonate and finally water. The toluene is removed in vacuo and thecrude product pyrone ester is purified either by short path distillationor by crystallisation and trituration to give (after removal of residualsolvent by evaporation in vacuo) the coumalic acid methyl ester (78.8 g,99% purity, 64% yield).

Preparation 3

Conversion of coumalic acid, methyl ester to 3-bromocoumalic acid,methyl ester A solution of pyrone ester (39 g, 95% purity) in aceticacid is added over 3.5 hr to a refluxing solution of pyridiniumtribromide (105 g) in glacial acetic acid (233 g). The mixture is heldat reflux (85° C.->107° C.) for 3 hr then cooled to ambient. Water isadded and the crude product is isolated by filtration then washed withwater. The crude product is purified by recrystallisation from tolueneand iso-hexane to give 3-bromocoumalic acid, methyl ester (46 g, 82%yield).

Preparation 4

Conversion of 3-bromocoumalic acid, methyl ester to methyl4-bromo-2-naphthoate Isoamyl nitrite (24.2 g) and a solution ofanthranilic acid (28.0 g) in ethylene glycol dimethyl ether (90 g) areadded over 3 h to a refluxing solution of 3-bromo coumalic acid, methylester (23.3 g) in ethylene glycol dimethyl ether (135.8 g) in thepresence of catalytic trichloroacetic acid (0.165 g). The reaction isrefluxed for a further 1 hr after the end of addition to ensure completereaction. The reaction mass is cooled to 50° C., toluene (279 g) isadded and the mixture then cooled to ambient. The toluene solution iswashed with sodium hydroxide solution (75 mL, 2M), sodium bisulphitesolution (75 mL, 5%), water (75 mL), hydrochloric acid and water again.The toluene solution is then concentrated in vacuo to give methyl4-bromo-2-naphthoate (30 g, 85% purity, 93% yield).

Preparation 5

Conversion of methyl 4-bromo-2-naphthoate to 4-bromo-2-naphthonitrileDimethylaluminium amide is prepared by the reaction of a solution oftrimethylaluminium in toluene (150 mL, 2M) with excess anhydrous ammonia(25.5 g) at −78° C. Excess ammonia is removed by evaporation at 110° C.and the dimethylaluminium amide solution is then charged to a solutionof the bromonaphthoate (39.8 g) in m-xylene (321.7 g) at 110° C. over 1hour. The reaction is held at 110° C. for a further hour and thenrapidly cooled to room temperature in ice. The reaction mass is drownedout into aqueous HCl (750, mL, 2M) over 1.5 hours at 5-10° C. Them-xylene solution is concentrated in vacuo to give the crude product,which is recrystallised from toluene/iso-hexane to give4-bromo-2-naphthonitrile (18.9 g, 54% yield).

Preparation 6

Conversion of methyl 4-bromo-2-naphthoate to 4-bromo-2-naphthonitrilevia 4-bromo-2-naphthamide To a Carius tube equipped with small magneticflea and protective outer metal casing is charged methyl4-bromo-2-naphthoate (1.18 g), aqueous ammonia (9 ml), potassium iodide(0.075 g) and methanol (2 ml). The apparatus is assembled, and loweredinto an oil bath at 130° C. The pressure rises to 4.25 bar. The mixtureis heated with stirring under these conditions for 66 h, after whichtime the assembly is removed from the oil bath and allowed to cool toambient temperature/pressure. The mixture is cooled to 0° C. to completecrystallisation, and filtered to remove the product. The product isdissolved in EtOAc (50 ml) and washed with 10% w/v aqueous Na₂CO₃ (2×10ml). The organic layer is separated, dried MgO₄) and the solvent removedin vacuo to give the product 4-bromo-2-naphthamide as colourless prisms(0.38 g, 94% str by GC area, 33% yield,).

To a 10 ml 1-necked round-bottomed flask equipped with magnetic stirrer,condenser and inert atmosphere is charged 4-bromo-2-naphthamide (0.093g) and thionyl chloride (2 ml). The mixture is heated under reflux for18 h, and the excess thionyl chloride is removed in vacuo to afford thecrude product 4-bromo-2-naphthonitrile as a yellow solid.

¹H nmr (CDCl₃): 8.15 (s, 1H, ArH), 8.24 (d, 1H, J=7.4 Hz, ArH),7.90-7.62 (m, 4H, ArH).

MS: 233 (M⁺), 231 (M⁺), 152, 125, 76.

Preparation 7 Conversion of methyl 4-bromo-2-naphthoate to4-bromo-2-naphthonitrile Via 4-bromo-N-hydroxy-2-naphthamide

To a 100 ml 2-necked round-bottomed flask equipped with magneticstirrer, graduated pressure equalised dropping funnel and inertatmosphere is charged bromonaphthoate (2.69 g), hydroxylaminehydrochloride (2.78 g) and methanol (16 ml). 5 M Methanolic KOH (10 ml.)is added dropwise over 40 min to the vigorously stirred suspension atroom temperature. An exotherm and an orange colouration is noted on eachaddition. The reaction mixture (beige suspension) is stirred at roomtemperature for 17 h after addition of base. The reaction mixture isconcentrated to ca. half volume in vacuo (water bath <45° C.) and a 1:1mixture of water/glacial acetic acid (50 ml) added with vigorousstirring. Stirring is continued for 40 min. and a further portion of 1.1water/glacial acetic acid 20 ml) added when the suspension becomes toothick to stir. Stirring is continued for 1 h, and the product filteredoff under reduced pressure and washed with cold water (3×15 ml). Theproduct hydroxamic acid is dried in the vacuum oven at 70° C. to give4-bromo-N-hydroxy-2-naphthamide as a beige powder (2.2 g, 76% str. by LCarea, 76% yield,).

To an oven dried 250 ml 2-necked round-bottomed flask equipped withmagnetic stirrer, condenser, septum and inert atmosphere is charged4-bromo-N-hydroxy-2-naphthamide (2.0 g) and fluorobenzene (80 ml).Phosphorous tribromide (1.8 ml) is added dropwise over 10 min to thestirred suspension at room temperature and the mixture heated to reflux(85° C.) whereupon a clear orange solution is obtained. Reflux iscontinued for 18 h, and the solution allowed to cool. The crude reactionmixture is poured into saturated aqueous NaHCO₃ solution (50 ml) and theproduct extracted with toluene (3×50 ml). The combined organic extractsare washed with brine (50 ml) and the solvent removed in vacuo. Theresidue is crystallised from methanol to give the product4-bromo-2-naphthonitrile as pale yellow prisms (0.73 g).

The ¹H nmr and mass spectra of the above end product corresponds tothose previously 30 obtained.

Preparation 8 Conversion of Coumalic Acid to3-bromo-2-oxo-2H-pyran-5-carbonitrile (3-bromocoumalonitrile) Via2-oxo-2H-pyran-5-carbonitrile (coumalonitrile)

Coumalic acid (3.91 g) and thionyl chloride (31 ml) are charged to a 100ml 2-neck round bottomed flask equipped with condenser, magnetic stirrerand inert atmosphere, and the suspension heated to reflux for 1 h. Theclear yellow solution is allowed to cool, and the excess thionylchloride removed in vacuo. Sulfamide (3.22 g) is added, and the solidmixture heated to 120° C. (bath temp.) for 1 h. The acid chloride meltsafter a few seconds, and HCl is vigorously evolved. After ca. 15 min, ared foam is obtained, which on further heating collapses to a dark redviscous oil. After 1 h, the reaction mixture has solidified. Thereaction mixture is allowed to cool, and transferred to a separatingfunnel with 10% w/v aqueous NaHCO₃ solution (150 ml) (heating with thelatter being necessary to remove the crude product from the flask). Theproduct is extracted with CH₂Cl₂ (2×50 ml) and the combined organiclayers washed with sat. NaCl solution (100 ml). The extracts are dried(MgSO₄) and the solvent removed in vacuo. The residue is purified bycrystallisation from MeOH (2 ml) at 0° C. The product coumalonitrile isobtained as dark orange prisms (1.7 g). Coumalonitrile (2.0 g),pyridinum bromide perbromide (5.28 g), dimethoxy ethane (13 g) andtoluene (12,98) are charged to a 100 ml 2-neck round bottomed flaskequipped with condenser, magnetic stirrer and inert atmosphere, andheated under reflux for 4 h. The reaction mixture is poured into water(100 ml) and extracted with CH₂Cl₂ (3×100 ml). The extracts are dried(MgSO₄) and the solvent removed in vacuo. The residue is swirled withether (20 ml) and the extracts decanted off. The residue is purified bycrystallisation from acetone to give the3-bromo-2-oxo-2H-pyran-5-carbonitrile as an orange powder (1.25 g, 81%str. by LC area, 31% yield).

¹H nmr (CDCl₃): 7.74 (d, 1H, J=2.5 Hz, H_(a)), 8.04 (d, 1H, J=2.2 Hz,H_(b)).

MS: 201 (M⁺), 199 (M⁺), 173, 171, 144, 142, 120, 64, 29.

Preparation 9

Conversion of 3-bromo-2-oxo-2H-pyran-5-carbonitrile(3-bromocoumalonitrile) to 4-bromo-2-naphthonitrile Solutions ofanthranilic acid (1.8 g, 12.8 mmol) in DME (10 ml) and isoamyl nitrite(1.54 g, 12.8 mmol) in DME (10 ml, 8.7 g) are added dropwise over 20 minto a stirred solution of 3-bromocoumalonitrile (1.15 g, 4.6 mmol) andtrichloroacetic acid (0.047 g, 0.29 mmol) in DME (40 ml) held at reflux.The mixture is refluxed for a further 10 min, allowed to cool and pouredinto water (100 ml). The product is extracted with CH₂Cl₂ (2×50 ml) andthe volatiles removed in vacuo. The product crystallises from theresidual amyl alcohol at −20° C. and the dirty orange solid is collectedby filtration in vacuo, and dried in the oven at 40° C. to give4-bromo-2-naphthonitrile (0.81 g, 49% yield).

Preparation 10 Conversion of 1,2,3,4-Tetrahydronaphthalene to5,6,7,8-tetrahydronaphthalene-2-carbonitrile

1,2,3,4-Tetrahydronaphthalene (3.3 g), aluminium chloride (6.7 g),cyanogen bromide (5.5 g) and carbon disulphide (70 ml) were heatedtogether under reflux for 8 hours however this achieved negligiblereaction, the mixture was accordingly concentrated by distilling outsolvent at atmospheric pressure until the temperature of the reactionmixture rose to 60° C. Stirring was continued at 60° C. for 8 hours, themixture was cooled, chloroform (100 ml) was added and the resultingmixture then added slowly to a stirred mixture of concentratedhydrochloric acid (3 g) and 50:50 ice water (150 ml) at 0° C. Theresulting phases were separated, the aqueous layer was extracted withchloroform (2×100 ml), the combined organic phases were washed withsaturated aqueous sodium bicarbonate solution (150 ml) and water (2×50ml), they were dried (MgSO₄) and solvent removed by evaporation in vacuoto give crude product (3.8 g) comprising a 3:1 mixture of5,6,7,8-tetrahydronaphthalene-2-carbonitrile and5,6,7,8-tetrahydronaphthalene-1-carbonitrile. This was purified bydistillation under reduced pressure to give5,6,7,8-tetrahydronaphthalene-2-carbonitrile in 40% overall yield.

Conversion of 5,6,7,8-tetrahydronaphthalene-2-carbonitrile to4-bromo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

Bromine (2.5 g, 15.6 mmol) was added cautiously to a stirred mixture of5,6,7,8-tetrahydronaphthalene-2-carbonitrile (2 g, 12 mmol) and ferricbromide (4.7 g, 15.6 mmol) in carbon tetrachloride (20 ml) at 10° C. Themixture was stirred at ambient temperature for 8 hours, it was worked upby adding to dilute aqueous hydrochloric acid and extracting withchloroform followed by removal of solvent by evaporation in vacuo togive the crude product as a brown oil (5.74 g, 45% purity by gc area,86% yield). The product was purified by chromatography on silica gelusing 1:9 ethyl acetate:hexane eluent to give4-bromo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile as a mixture ofisomers.

Preparation 11 Conversion of 1,2,3,4-tetrahydronaphthalene to5-bromo-1,2,3,4-tetrahydronaphthalene and6-bromo-1,2,3,4-tetrahydronaphthalene

Bromine (66.1 g, 0.41 mol)) was added over 3 hours, with stirring at 5°C. to 10° C., to the 1,2,3,4-tetrahydronaphthalene (50 g, 0.374 mol)along with a small piece of iodine (0.25 g, 0.98 mmol). Stirring wascontinued at ambient temperature for 6 hours and the mixture was thenpoured slowly into a stirred saturated aqueous solution of sodiumsulphite (200 ml) at 10° C. Stirring was continued for 15 minutes, theresulting mixture was extracted with methylene chloride (3×50 ml), thecombined organic extracts were washed with water (200 ml), dried (MgSO₄)and solvent removed by evaporation in vacuo to give5-bromo-1,2,3,4-tetrahydronaphthalene along with the6-bromo-1,2,3,4-tetrahydronaphthalenec isomer (86 g, 89.7% purity ofcombined mono-brominated isomers present in circa 3:2 ratio, combinedmono-bromo isomer yield 96%).

Conversion of 5-bromo-1,2,3,4-tetrahydronaphthalene and6-bromo-1,2,3,4-tetrahydronaphthalene to5,6,7,8-tetrahydronaphthalene-2-carbonitrile Along with5,6,7,8-tetrahydronaphthalene-1-carbonitrile isomer

A mixture of 5-bromo-1,2,3,4-tetrahydronaphthalene and 6-bromo-1,2,3,4tetrahydronaphthalene (20 g), copper (I) cyanide (8.6 g) and anhydrousN-methylpyrrolidinone (41.3 g) were stirred under dry nitrogen at 130°C. for 40 h. The mixture was cooled to ambient temperature, furtherN-methylpyrrolidinone (10 g) was added along with saturated aqueousbrine (30 ml), the resulting mixture was stirred at ambient for 3 hoursand filtered to remove solids. The filtrates were extracted withn-hexane (3×50 ml). The combined organic extracts were washed with water(100 ml), dried (MgSO₄) and evaporated in vacuo to give crude product(16.2 g). This was purified by distillation to give5,6,7,8-tetrahydronaphthalene-2-carbonitrile along with regioisomer(13.2 g, 95% purity, 84% yield).

Preparation 12 Conversion of 5-bromo-1,2,3,4-tetrahydronaphthalene and6-bromo-1,2,3,4-tetrahydronaphthalene to5,6,7,8-tetrahydronaphthalene-1-carboxylic acid and5,6,7,8-tetrahydronaphthalene-rboxylic acid

n-Butyl lithium (9.6 ml of 2.5M solution in hexane) was added dropwiseover 30 minutes to a stirred solution of5-bromo-1,2,3,4-tetrahydronaphthalene in mixture with its regioisomer6-bromo-1,2,3,4-tetrahydronaphthalene (5 g) in dry THF (125 ml) andhexane (35 ml) at −70° C., stirring was continued at −78° C. for 30minutes, carbon dioxide gas was bubbled through the mixture at −70° C.until no further exotherm was evident, carbon dioxide gas addition wascontinued for a further 10 minutes as the reaction was allowed to warmto ambient temperature, the mixture was poured into 2M aqueoushydrochloric acid (100 ml) and the resulting mixture was extracted withdiethyl ether (3×50 ml). The combined organic extracts were washed withwater (100 ml) and were then extracted with 10% aqueous sodium carbonatesolution (3×50 ml). The combined aqueous carbonate extracts wereacidified carefully by addition of 2M hydrochloric acid to adjust the pHto pH 1. The resulting mixture was extracted with diethyl ether (3×50ml), the combined organic extracts were washed with water (50 ml) anddried (MgSO₄) before solvent was removed by evaporation in vacuo to givethe crude product in 64% yield comprising a mixture of regioisomers of5,6,7,8-tetrahydronaphthalene carboxylic acid. This mixture was purifiedby repeated recrystallisation from ethyl acetate to give5,6,7,8-tetrahydronaphthalene-2-carboxylic acid as crystallised solid in93% purity along with 5,6,7,8-tetrahydronaphthalene-1-carboxylic acid asthe major component present in the crystallisation mother liquors.

Conversion of 5,6,7,8-tetrahydronaphthalene-2-carboxylic acid to5,6,7,8-tetrahydronaphthalene-2-carbonitrile

Acetyl chloride (5 g, 64 mmol) is added dropwise to dry methanol (150ml) with stirring at ambient temperature under dry nitrogen. Stirring iscontinued for 15 minutes, 5,6,7,8-Tetrahydronaphthalene-2-carboxylicacid (1 g, 5.7 mmol) is added, the mixture is stirred at ambienttemperature for 10 hours and solvent removed by evaporation in vacuo togive methyl 5,6,7,8-tetrahydronaphthalene-1-carboxylate. This is thenconverted to 5,6,7,8-tetrahydronaphthalene-2-carbonitrile using the sameprocedure described above for conversion of methyl 4-bromo-2-naphthoateto 4-bromo-2-naphthonitrile using dimethylaluminium amide.

Preparation 13 Conversion of4-bromo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile to4-bromo-2-naphthonitrile

4-Bromo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.1 g) was heatedwith 10% palladium on carbon (1.65 g) under air at 200° C. to 210° C.for 22 hours to give crude 4-bromo-2-naphthonitrile as seen by gc(approximately 75% yield by gc area).

EXAMPLES Example 1 Conversion of 4-bromo-2-naphthonitrile to3-cyano-1-naphthoic acid via metallo-dehalogenation and carboxylation

To a 50 ml 4-neck round bottomed flask equipped with a magnetic stirrer,thermometer, septum, CO₂ inlet, N₂ inlet/bubbler and external dryice/acetone cooling bath is charged (0.35 g, 1.25 mmol), anhydroushexane (2 ml) and anhydrous THF (8 ml). The suspension is cooled to −75°C. and BuLi (0.6 ml) added dropwise over 20 min to the vigorouslystirred suspension. The bright red solution is stirred for a further 5min and then carbon dioxide bubbled very slowly through the reactionmixture with external cooling. The quenching reaction is veryexothermic—maximum temperature reached is −65° C. Reaction is judgedcomplete when no further temperature increase is observed upon additionof carbon dioxide. The mixture is stirred at −65° C. for a further 10min, and then added cautiously to 2 M HCl. The product is extracted withethyl acetate (3×50 ml), the combined extracts dried (MgSO₄) and thesolvent removed in vacuo to give 3-cyano-1-naphthoic acid (circa 20%yield).

¹H nmr (D₆DMSO): 7.69-7.87 (m, 2H, 2×ArH), 8.14 (d, 1H, J=7.9 Hz, ArH),8.28 (d, 1H, J=1.5 Hz, ArH), 8.79 (s, 1H, ArH), 8.85 (d, 1H, J=8.4 Hz,ArH).

MS: 197 (M⁺), 180, 152, 125, 29, 18.

Example 2 3-cyano-1-naphthoic acid via carbonylation

Bis(triphenylphosphine)palladium (II) chloride (0.77 g) inN-methylpyrrolidinone (170 g), (10 g), triphenyl phosphine (0.57 g), andtriethylamine (11 g,) are mixed in a nitrogen inerted pressure vessel(Parr reactor) at ambient temperature. Water (15.5 g) is added and thereactor is repeatedly purged with argon to remove residual air oroxygen. The reactor is vented and then pressurised with carbon monoxideto 7 bar absolute pressure (6 bar gauge pressure) and the mixturestirred at 85 C for 10 hours, maintaining carbon monoxide pressurewithin the reactor at 6 barg. The mixture is cooled to 50 C and ventedto atmospheric pressure, and the reaction mixture then filtered througha bed of celite to remove solids. The filter cake is washed with toluene(160.5 g) and then with water (124 g). The combined filtrates and washesare allowed to settle and the lower aqueous layer separated. The toluenelayer is extracted with water (2×124 g). The combined aqueous phase andaqueous extracts were washed with toluene (120 g), 2M hydrochloric acid(64.5 ml) are added to the aqueous solution over 30 minutes withstirring at 25 to 30 C. The organic layer is separated off and retained,the aqueous layer is extracted with toluene (2×120 g). The combinedorganic layer and toluene extracts are mixed with water (62 g) and 2Msodium hydroxide solution (16.2 ml) to extract the product into theaqueous phase. The organic phase is extracted with further water (62 g)plus 2M sodium hydroxide solution (16.2 ml). The combined aqueousextracts are mixed with dichloromethane (350 g) and the mixtureacidified by addition of 2M hydrochloric acid (43 ml) over 30 minutes at25 to 30 C. The lower organic phase is separated and retained, theaqueous phase is extracted with further dichloromethane (100 g). Thecombined dichloromethane solution and extract are washed with 2Mhydrochloric acid (21.5 ml), toluene (120 g) is added anddichloromethane is removed by evaporation under reduced pressure toleave a toluene solution of the product. This solution is heated to 60C, iso-hexane (300 g) is added over 30 minutes at 60 C, and the mixturecooled over 3 hours to 5 C so as to crystallise the product, which isisolated by filtration. The product is washed with pre-cooled iso-hexaneat 0 C to 5 C and it is then dried overnight in a vacuum oven at 40 C(5.66 g, 65% yield).

The obtained product is confirmed by analysis to be the same as inExample 1.

CONCLUSIONS

The new routes described herein offer significantly improved means forlarge scale manufacture of naphthalene cyanoacid (1) compared withmethodology available from the chemical literature. These new routesoffer advantage in terms of significantly improved through-route yield(with considerable potential for yet further yield improvement), theyavoid the large scale process operability difficulties associated withthe previous literature chemistry, they give product of lower cost ofmanufacture and they avoid the effluent toxicity and reagent toxicityassociated with use of stoichiometric mercury salts specified in thepreviously published chemistry to such products.

1. A process for preparing a compound of formula (1)

wherein X, and/or Y₁, and Y₂ are independently H, cyano, nitro,trifluoromethoxy, trifluoromethyl, alkoxy, or alkyl, and R is H oralkyl, wherein a) when R═H, the process comprises metallo-dehalogenationfollowed by carboxylation of a compound of formula (12)

wherein X, Y₁ and Y₂ are as defined above, and Hal is Br, I or Cl; or b)when R═H or alkyl, the process comprises palladium-mediatedcarbonylation of a compound of formula (12)

with the proviso that the compound 1-iodo-3-cyano-2-methoxynaphthaleneis excluded, followed by solvolysis of the carbonylated compound.
 2. Theprocess for preparing the compound of formula (1) according to claim 1wherein, step a) is carried out by treatment of the compound of formula(12) with an alkyl-lithium reagent followed by reaction of the lithiatedintermediate with carbon dioxide and then acidification.
 3. A compoundof formula (12),

wherein X, Y₁ and Y₂ are independently H, cyano, nitro,trifluoromethoxy, trifluoromethyl, alkoxy, or alkyl and Hal is Br, I orCl, with the proviso that the compounds1-iodo-3-cyano-2-methoxynaphthalene and1-chloro-3-cyano-2-methoxynaphthalene are excluded.
 4. The processaccording to claim 1, for preparing a compound of formula (12,Y₁═Y₂═X═H),

wherein Hal is Br, I or Cl, wherein the process comprises a reactionsequence selected from the group consisting of: (i) (a) treating malicacid with strongly acid dehydrating media to give coumalic acid; (b)esterifying coumalic acid to give a pyrone ester; (c) brominating thepyrone ester to give a 3-bromo coumalic ester; (d) reacting the 3-bromocoumalic ester (10) with in situ generated benzyne followed bydecarboxylation to give a bromonaphthoate (11); and (e) converting thebromonaphthoate (11) to 1-bromo-3-cyano naphthalene; (ii) (a) treatingmalic acid with a strongly acid dehydrating media to give coumalic acid;(b) converting coumalic acid into coumalonitrile and subsequentlybrominating to give 3-bromo-5-coumalonitrile; and then (c) converting3-bromo-5-coumalonitrile into 1-bromo-3-cyano naphthalene bycycloaddition of in situ generated benzyne, followed by subsequentdecarboxylation and (iii) (a) cyanation of 1,2,3,4-tetrahydronaphthalenefollowed by bromination to give compound (63)

(b) bromination of 1,2,3,4-tetrahydronaphthalene followed bycyanodebromination, followed by bromination to give the compound offormula (63); or (c) bromination of 1,2,3,4-tetrahydronaphthalenefollowed by carboxylation followed by conversion to the6-cyano-1,2,3,4-tetrahydronaphthalene followed by bromination to givecompound (63); followed by c1) oxidative aromatization of compound (63)into 1-bromo-3-cyano naphthalene.
 5. The process according to claim 4,wherein the reaction of the ester with benzyne in step (d) of process(i) generates an intermediate having structure (15)

which intermediate is decarboxylated to give the bromonaphthoate.
 6. Theprocess according to claim 4, wherein step (e) of process (i) is carriedout by means selected from the group consisting of: e1) reaction of thebromonaphthoate compound with ammonia to give compound (18)

followed by dehydration to give the cyano compound; e2) reaction of thebromonaphthoate compound with hydroxylamine or a salt thereof to givecompound (20);

followed by dehydration to give the cyano compound; and e3) adding asolution of Me₂AlNH₂ to a solution of the bromonaphthoate compound in ahigh-boiling solvent and heating the mixture to reflux, followed byrapid conversion to the cyano compound.
 7. The compound of formula (20)


8. The compound of formula (18)


9. The compound which is 3-bromo-5-coumalonitrile.
 10. The compound offormula (63)


11. The process according to claim 4, wherein the strongly aciddehydrating media is oleum.
 12. The process according to claim 6,wherein the high-boiling solvent is m-xylene.
 13. The bromonaphthoatecompound of formula (11),